Use of gastrointestinally administered porous enteron sorbent polymers to prevent or treat radiation induced mucositis, esophagitis, enteritis, colitis, and gastrointestinal acute radiation syndrome

ABSTRACT

Disclosed herein are compositions and methods for preventing or treating acute or chronic oral mucositis, esophagitis, enteritis, colitis, or gastrointestinal acute radiation syndrome (GI-ARS) caused by radiation exposure, using one or more enteron sorbent polymers administered gastrointestinally (e.g. orally, via feeding or gastric tube, via ostomy, or rectally).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/515,328, filed Mar. 29, 2017, now published U.S.Patent Application No. 2017-0216345, which is a National StageApplication filed under 35 U.S.C. § 371 of International Application No.PCT/US2015/053622, filed Oct. 2, 2015, which claims the benefit of U.S.Provisional Application No. 62/058,864, filed Oct. 2, 2014; thedisclosures of which are incorporated herein by reference in theirentireties.

TECHNICAL FIELD

The disclosed inventions are in the field of porous enteron sorbentpolymers. The disclosed inventions are also in the field of reducing,preventing, and/or treating oral mucositis, esophagitis, radiationenteritis, colitis and gastrointestinal acute radiation syndrome.

BACKGROUND

Wide presence of radioactive material for therapeutic, energy, orweapons underscores the need for medical preparedness for effectivetreatment of either accidental or intentional exposure. High energyradiation exposure (e.g. gamma radiation or X-rays) from cancerradiotherapy, or from acute radiation exposure, such as from the broaddissemination of radioactive materials in water or air (e.g. a “dirtybomb”, a nuclear power catastrophe, or a nuclear explosion) canpenetrate the body and cause harmful effects such as cell death andtissue damage. Cosmic rays and solar flares are another form of highenergy radiation experienced during solar flares, at high altitudes andin outer space, which can lead to similar tissue injury. When thegastrointestinal (GI) tract is affected, radiation can lead to oralmucositis (head and neck radiation), esophagitis typically thoracicradiation), and radiation enteritis and colitis (due to abdominal andpelvic radiation), and more broadly, gastrointestinal acute radiationsyndrome (GI-ARS). Currently there is no medical therapy orcountermeasure approved to prevent, treat or mitigate radiation toxicitypost-exposure, other than secondary and supportive care.

One of the acute physiological effects of irradiation is acute radiationsyndrome (ARS), which first manifests in the gastrointestinal tract(GI-ARS). The acute phase occurs within days of radiation exposure,resulting from loss of intestinal clonogenic cells that lead to loss ofepithelial crypts and ulceration. Symptoms and complications includeweight loss, diarrhea, dehydration, susceptibility to infection, andtranslocation of bacteria and toxins as the intestinal mucosal barrieris compromised. Bacterial translocation from the intestine to blood andendotoxemia can lead to septic shock and death.

Radiation injury can also lead to delayed effects of acute radiationexposure (GI-DEARE). Similar to ARS, delayed effects of radiationexposure also have adverse health effects. This is evident from theJapanese survivors of high-dose radiation exposure, and also fromradiation oncotherapy. Patients receiving radiation cancer treatment canfrequently develop both acute and delayed GI enteropathies months andyears post-therapy. In the delayed effects, there is a high incidence ofGI symptoms of diarrhea, constipation, obstruction, fistulation, severeinflammatory response syndrome and sepsis, occurring in 50% of thepatients with pelvic tumors receiving therapy.

Characterization of GI-ARS links to other syndromes, such as thehematopoetic system (H-ARS). All radiation doses that induce GI-ARS willhave a major impact on bone marrow. This will affect the severity of GIinflammation and infection due to bacterial translocation through theimpaired gut epithelium. The major organ sequelae to high-dose radiationinvolve other organ damage as well. Lung injury, for example, resultsfrom the DEARE. Cytokines, bacterial toxins and other inflammatorymediators play an important role in the illness. Decreasing inflammationmay offer a promising therapy. For example, a number of studiescorrelated reduction of inflammation with anti-cancer efficacy.

Each of these conditions is typically associated with high morbidity andmortality. Therefore, it is imperative to come up with treatments forthe prevention (termed a radioprotector) and mitigation (termed amitigator) of both the acute and delayed adverse effects of radiationexposure.

SUMMARY

Enteron sorbent polymers are uniquely suited to prevent or treat theseconditions. Enteron sorbent polymer are novelgastrointestinally-administered (e.g. administration via oral,nasogastric or gastric tube, ostomy, or rectal routes), topicalanti-inflammatory therapies for the GI tract that uses non-absorbable,highly-porous enteron sorbent polymers. Enteron sorbent polymerssequester intra-luminal cytokines, bacterial toxins and other mediatorsbased on pore capture and surface adsorption and excrete them from thebody. Enteron sorbent polymers can potentially reduce the risk of deathin GI-ARS by reducing intestinal inflammation, gut permeability,bacterial and toxin translocation from the gut lumen to the systemiccirculation, symptoms of enterocolitis such as diarrhea, the systemicinflammatory response syndrome, and septicemia.

In radiation cancer treatment, enteron sorbent polymers are gamma stableand radio-lucent and should remain stable and not interfere withradiotherapy. By mitigating GI enteritis and other associatedconditions, enteron sorbent polymers may be able to minimize adverseevent related radiation treatment de-escalation. Alternatively, it canaide in escalation of the radiation dose and concurrent chemotherapyaimed at improving tumor killing. Enteron sorbent polymers can serve asa radioprotector and/or a radiation mitigator post-exposure.

In prophylaxis of radiation enteritis due to mass radiation exposure orduring a space mission, enteron sorbent polymers can beself-administered. They can also serve as a GI radiation mitigator aftera high-dose exposure.

Preferred enteron sorbent polymers include cross-linked polymericmaterials derived from the reaction of a cross-linker with one or moreof the following polymerizable monomers: divinyl-benzene, styrene,ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate,butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate,ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene,vinylbenzyl alcohol, vinylformamide, methyl methacrylate, and methylacrylate.

In certain embodiments, the solid form of the enteron sorbent polymer ischaracteristically porous. Some solid forms are characterized as havinga pore structure having a total volume of pore sizes in the range offrom 10 Å to 250,000 Å greater than 0.3 cc/g and less than 3.0 cc/g drypolymer; wherein the ratio of pore volume between 10 Å to 250,000 Å indiameter to pore volume between 250 Å to 250,000 Å in diameter of thecross-linked polymeric material is smaller than 7:1 and wherein theratio of pore volume between 10 Å to 250,000 Å in diameter to porevolume between 50 Å to 250,000 Å in diameter of the cross-linkedpolymeric material is less than 2:1.

In certain embodiments, the enteron sorbent polymers can be made in beadform having a diameter in the range of 0.1 microns to 2 centimeters.Certain polymers are in the form of powder, beads or other regular orirregularly shaped particulates.

In some methods, the undesirable molecules are inflammatory mediatorsand stimulators comprise cytokines, superantigens, monokines,chemokines, interferons, free radicals, proteases, arachidonic acidmetabolites, prostacyclins, beta endorphins, anandimide,2-arachadonylglycerol, tetrahydrobiopterin, serotonin, histamine,bradykinin, soluble CD40 ligand, bioactive lipids, oxidized lipids,cell-free hemoglobin, growth factors, glycoproteins, prions, toxins,bacterial and viral toxins, endotoxins, drugs, vasoactive substances,foreign antigens, and antibodies.

Some methods of the invention can be performed such that the enteronsorbent polymer is gastrointestinally administered (e.g. orally,rectally, via nasogastric or gastric tube, or via ostomy within thehuman body).

In some embodiments, the plurality of solid forms of enteron sorbentpolymer comprises particles having a diameter in the range for 0.1micrometers to 2 centimeters.

Preferred enteron sorbent polymers are biocompatible.

In still yet another further embodiment, the present invention relatesto a method of manufacturing enteron sorbent polymer comprising abiocompatible surface coated polymer system comprising an organic phaseand an aqueous phase, the method comprising: forming the organic phasecomprising polymerizable monomers and at least one initiator; formingthe aqueous phase comprising at least one dispersant agent, at least onefree radical inhibitor, and at least one buffering agent; dispersing theorganic phase into the aqueous phase by agitation to form a suspensionof organic droplets; and polymerizing the organic phase by heating thesuspension of the organic phase droplets coated with the dispersingagent to thereby form the biocompatible surface coating on the enteronsorbent polymer.

In another embodiment, the present invention relates to an enteronsorbent polymer with a biocompatible coating comprising at least onecrosslinking agent for making the enteron sorbent polymer and at leastone dispersing agent whereby the dispersing agent forms a biocompatiblesurface on the enteron sorbent polymer.

In another embodiment, the biocompatibilizing polymer comprisespoly(N-vinylpyrrolidinone). In still another embodiment, thebiocompatibilizing polymer is selected from a group comprisingpoly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate),poly(dimethylaminoethyl methacrylate), salts of poly(acrylic acid),salts of poly(methacrylic acid), poly(diethylaminoethyl methacrylate),poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate),poly(N-vinylpyrrolidinone), poly(vinyl alcohol) and mixtures thereof. Inanother embodiment, the salts may be sodium and potassium salts and instill another embodiment, the salts are water-soluble salts.

In yet another embodiment, the dispersing agent is selected from a groupcomprising hydroxyethyl cellulose, hydroxypopyl cellulose,poly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate),poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate),poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethylacrylate), poly(diethylamimoethyl methacrylate), poly(diethylaminoethylacrylate), poly(vinyl alcohol), salts of poly(methacrylic acid), andsalts of poly(acrylic acid) and mixtures thereof.

Certain enteron sorbent polymers useful in the invention are porouspolymers prepared from the polymerizable and copolymerizable monomers ofstyrene, divinylbenzene, ethylvinylbenzene, and the acrylate andmethacrylate monomers such as those listed below by manufacturer. Rohmand Haas Company, (now part of Dow Chemical Company): (i) porous enteronsorbent polymers such as Amberlite™ XAD-1, Amberlite™ XAD-2, Amberlite™XAD-4, Amberlite™ XAD-7, Amberlite™ XAD-7HP, Amberlite™ XAD-8,Amberlite™ XAD-16, Amberlite™ XAD-16 HP, Amberlite™ XAD-18, Amberlite™XAD-200, Amberlite™ XAD-1180, Amberlite™ XAD-2000, Amberlite™ XAD-2005,Amberlite™ XAD-2010, Amberlite™ XAD-761, and Amberlite™ XE-305, andchromatographic grade enteron sorbent polymers such as Amberchrom™ CG71,s,m,c, Amberchrom™ CG 161,s,m,c, Amberchrom™ CG 300,s,m,c, andAmberchrom™ CG 1000,s,m,c. Dow Chemical Company: Dowex™ Optipore™ L-493,Dowex™ Optipore™ V-493, Dowex™ Optipore™ V-502, Dowex™ Optipore™ L-285,Dowex™ Optipore™ L-323, and Dowex™ Optipore™ V-503. Lanxess (formerlyBayer and Sybron): Lewatit™ VPOC 1064 MD PH, Lewatit™ VPOC 1163,Lewatit™ OC EP 63, Lewatit™ S 6328A, Lewatit™ OC 1066, and Lewatit™60/150 MIBK. Mitsubishi Chemical Corporation: Diaion™ HP 10, Diaion™ HP20, Diaion™ HP 21, Diaion™ HP 30, Diaion™ HP 40, Diaion™ HP 50, Diaion™SP70, Diaion™ SP 205, Diaion™ SP 206, Diaion™ SP 207, Diaion™ SP 700,Diaion™ SP 800, Diaion™ SP 825, Diaion™ SP 850, Diaion™ SP 875, Diaion™HP 1MG, Diaion™ HP 2MG, Diaion™ CHP 55A, Diaion™ CHP 55Y, Diaion™ CHP20A, Diaion™ CHP 20Y, Diaion™ CHP 2MGY, Diaion™ CHP 20P, Diaion™ HP20SS, Diaion™ SP 20SS, Diaion™ SP 207SS. Purolite Company: Purosorb™ AP250 and Purosorb™ AP 400, and Kaneka Corp. Lixelle beads.

The general description and the following detailed description areexemplary and explanatory only and are not restrictive of the invention,as defined in the appended claims. Other aspects of the presentinvention will be apparent to those skilled in the art in view of thedetailed description of the invention as provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The summary, as well as the following detailed description, is furtherunderstood when read in conjunction with the appended drawings. For thepurpose of illustrating the invention, there are shown in the drawingsexemplary embodiments of the invention; however, the invention is notlimited to the specific methods, compositions, and devices disclosed. Inaddition, the drawings are not necessarily drawn to scale. In thedrawings:

FIG. 1 illustrates a Pore Volume vs. Pore Diameter Plot, (dV/dD vs. D)for Adsorbent CY12030 Measured by Nitrogen Desorption Isotherm;

FIG. 2 illustrates a Pore Volume vs. Pore Diameter Plot, (dV/d log D vs.D) for Adsorbent CY12030 Measured by Nitrogen Desorption Isotherm;

FIG. 3 illustrates a Pore Volume vs. Pore Diameter Plot, (dV/dD vs. D)for Adsorbent CY12031 Measured by Mercury Intrusion;

FIG. 4 illustrates a Pore Volume vs. Pore Diameter Plot, (dV/dD vs. D)for Adsorbent CY12031 Measured by Mercury Intrusion;

FIG. 5 shows a change in group mean body weight. C57BL/6 mice wereirradiated, 20 per group, with 13.5 Gy partial-body irradiation (with 5%of bone marrow shielded). Mice were treated with either 150 μL of water(control) or 150 μL of 50% enteron sorbent polymer slurry (treatment)twice a day for 15 days post 24-hour exposure. A second gavage withsterile water was administered to both control and treated groupsimmediately following the first gavage for extra hydration and/or washdown of beads from the first gavage. The mean weights of the survivingmice are plotted (top) along with the same plots showing StandardDeviation (bottom);

FIG. 6 shows a change in relative body weight. C57BL/6 mice wereirradiated, 20 per group, with 13.5 Gy partial-body irradiation (with 5%of bone marrow shielded). Mice were dosed with either 150 μL of water(control) or 150 μL of 50% enteron sorbent polymer slurry (treatment)twice a day for 15 days. A second gavage with sterile water wasadministered to both control and treated groups immediately followingthe first gavage for extra hydration and/or wash down of beads from thefirst gavage. The weights of the surviving mice are plotted as apercentage of the weight at the time of irradiation on day 0 (top) alongwith the same plots showing Standard Deviation (bottom);

FIG. 7 illustrates the percentage of control versus treated animals(Y-axis) that are still above a 25% weight loss threshold as a functionof time (days). At 25% weight loss, animals were sacrificed;

FIG. 8: illustrates animal survival following partial-body irradiation,with 5% of bone marrow shielded. Twenty C57BL/6 mice per group wereirradiated and maintained on acidified water. Mice were dosed witheither 150 μL of water (control) or 150 μL of 50% enteron sorbentpolymer slurry (treatment) twice a day for 15 days post 24-hourexposure. A second gavage with sterile water was administered to bothcontrol and treated groups immediately following the first gavage forextra hydration and/or wash down of beads from the first gavage. Micewere checked daily and euthanized when moribund or when they exceeded25% weight loss from baseline;

FIG. 9: depicts Kaplan-Meier survival curves of the time to death in thecontrol and treatment populations; and

FIG. 10: presents data for animal diarrhea post-13.5 Gy partial-bodyirradiation (with 5% of bone marrow shielded) (vehicle top, enteronsorbent polymer bottom). The plots illustrate the number of miceexhibiting diarrhea of a score 1 (mild) or 2 (severe) from days 4-8 (amand pm observations indicated by D4a, D4p, D5a, D5p etc.). Grey barsindicate the number of mice remaining in the study.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention may be understood more readily by reference to thefollowing detailed description taken in connection with the accompanyingfigures and examples, which form a part of this disclosure. It is to beunderstood that this invention is not limited to the specific materials,devices, methods, applications, conditions or parameters describedand/or shown herein, and that the terminology used herein is for thepurpose of describing particular embodiments by way of example only andis not intended to be limiting of the claimed invention. The term“plurality”, as used herein, means more than one. When a range of valuesis expressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms another embodiment. Allranges are inclusive and combinable.

It is to be appreciated that certain features of the invention whichare, for clarity, described herein in the context of separateembodiments, may also be provided in combination in a single embodiment.Conversely, various features of the invention that are, for brevity,described in the context of a single embodiment, may also be providedseparately or in any subcombination. Further reference to values statedin ranges include each and every value within that range.

The following definitions are intended to assist in understanding thepresent invention:

The term “biocompatible” is defined to mean the enteron sorbent polymeris capable of coming in contact with physiologic fluids, living tissues,or organisms without producing unacceptable clinical changes during thetime that the enteron sorbent polymer is in contact with the physiologicfluids, living tissues, or organisms. In some embodiments, it isintended that the enteron sorbent polymer is tolerated by the gut andalimentary canal of the organism. The enteron sorbent polymers of thepresent invention are preferably non-toxic. A biocompatible sorbent maybe a non-biodegradable, biodegradable, or resorbable polymer.

As used herein, the term “enteron sorbent polymer” includes adenteronsorbent polymers and abenteron sorbent polymers.

The coating/dispersant on the porous ST/DVB copolymer resin can imbuethe material with improved biocompatibility.

Some preferred enteron sorbent polymers comprise residues from one ormore monomers or containing monomers or mixtures thereof selected fromdivinylbenzene and ethylvinylbezene, styrene, ethylstyrene,acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate,octyl acrylate, cetyl methacrylate, cetyl acrylate, ethyl methacrylate,ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol,vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene,divinylnaphthalene, trivinylcyclohexane, divinylsulfone,trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate,trimethylolpropane triacrylate, trimethylolpropane diacrylate,pentaerythritol dimethacrylate, pentaerythritol trimethacrylate,pentaerythritol tetramethacrylate, pentaerythritol diacrylate,pentaerythritol triiacrylate, pentaerythritol tetraacrylate,dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate,dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate,dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, anddivinylformamide.

In some embodiments, the enteron sorbent polymer is a coated polymercomprising at least one crosslinking agent and at least one dispersingagent. The dispersing agent may be biocompatible. The dispersing agentscan be selected from chemicals, compounds or materials such ashydroxyethyl cellulose, hydroxypopyl cellulose, poly(hydroxyethylmethacrylate), poly(hydroxyethyl acrylate), poly(hydroxypropylmethacrylate), poly(hydroxypropyl acrylate), poly(dimethylaminoethylmethacrylate), poly(dimethylaminoethyl acrylate), poly(diethylamimoethylmethacrylate), poly(diethylaminoethyl acrylate), poly(vinyl alcohol),poly(N-vinylpyrrolidinone), salts of poly(methacrylic acid), and saltsof poly(acrylic acid) and mixtures thereof; the crosslinking agentselected from a group comprising divinylbenzene, trivinylbenzene,divinylnaphthalene, trivinylcyclohexane, divinylsulfone,trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate,trimethylolpropane triacrylate, trimethylolpropane diacrylate,pentaerythrital dimethacrylates, pentaerythrital trimethacrylates,pentaerythrital, tetramethacrylates, pentaerythritol diacrylates,pentaerythritol triiacrylates, pentaerythritol tetraacrylates,dipentaerythritol dimethacrylates, dipentaerythritol trimethacrylates,dipentaerythritol tetramethacrylates, dipentaerythritol diacrylates,dipentaerythritol triacrylates, dipentaerythritol tetraacrylates,divinylformamide and mixtures thereof. Preferably, the enteron sorbentpolymer is developed simultaneously with the formation of the coating,wherein the dispersing agent is chemically bound to the surface of theenteron sorbent polymer.

Some embodiments of the invention use an organic solvent and/orpolymeric porogen as the porogen or pore-former, and the resulting phaseseparation induced during polymerization yield porous polymers. Somepreferred porogens are benzyl alcohol, cyclohexane, cyclohexanol,cyclohexanol/toluene mixtures, cyclohexanone, decane, decane/toluenemixtures, di-2-ethylhexylphosphoric acid, di-2-ethylhexyl phthalate,2-ethyl-1-hexanoic acid, 2-ethyl-1-hexanol, 2-ethyl-1-hexanol/n-heptanemixtures, 2-ethyl-1-hexanol/toluene mixtures, isoamyl alcohol,n-heptane, n-heptane/ethylacetate, n-heptane/isoamyl acetate,n-heptane/tetraline mixtures, n-heptane/toluene mixtures,n-hexane/toluene mixtures, pentanol, poly(styrene-co-methylmethacrylate)/dibutyl phthalate, polystyrene/2-ethyl-1-hexanol mixtures,polystyrene/dibutyl phthalate, polystyrene/n-hexane mixtures,polystyrene/toluene mixtures, toluene, tri-n-butylphosphate,1,2,3-trichloropropane/2-ethyl-1-hexanol mixtures, 2,2,4-trimethylpentane (isooctane), trimethyl pentane/toluene mixtures, poly(propyleneglycol)/toluene mixtures poly(propylene glycol)/cyclohexanol mixtures,and poly(propylene glycol)/2-ethyl-1-hexanol mixtures.

Detailed embodiments of the present invention are disclosed herein; itis to be understood that the disclosed embodiments are merely exemplaryof the invention that may be embodied in various forms. Therefore,specific structural and functional details disclosed herein are not tobe interpreted as limits, but merely as a basis for teaching one skilledin the art to employ the present invention. The specific examples belowwill enable the invention to be better understood. However, they aregiven merely by way of guidance and do not imply any limitation.

The present biocompatible sorbent compositions are comprised of aplurality of pores. The biocompatible enteron sorbent polymers aredesigned to adsorb a broad range of toxins from less than 1 kDa to 1,000kDa. While not intending to be bound by theory, it is believed theenteron sorbent polymer acts by sequestering molecules of apredetermined molecular weight within the pores. The size of a moleculethat can be adsorbed by the enteron sorbent polymer will increase as thepore size of the enteron sorbent polymer increases. Conversely, as thepore size is increased beyond the optimum pore size for adsorption of agiven molecule, adsorption of said protein may or will decrease.

The enteron sorbent polymers used in the instant invention preferablyhave a biocompatible exterior surface coatings but are not absolutelynecessary, especially in certain circumstances, such as oral or rectaladministration. Certain of these coatings are covalently bound to theenteron sorbent polymer particle (beads, for example) by free-radicalgrafting. The free-radical grafting may occur, for example, during thetransformation of the monomer droplets into polymer beads. Thedispersant coating and stabilizing the monomer droplets becomescovalently bound to the droplet surface as the monomers within thedroplets polymerize and are converted into polymer. Biocompatibleexterior surface coatings can be covalently grafted onto the preformedpolymer beads if the dispersant used in the suspension polymerization isnot one that imparts biocompatibility. Grafting of biocompatiblecoatings onto preformed polymer beads is carried out by activatingfree-radical initiators in the presence of either the monomers or lowmolecular weight oligomers of the enteron sorbent polymers that impartbiocompatibility to the surface coating.

EXAMPLES Example 1: Enteron Sorbent Polymer Synthesis

Reactor Setup: A jacketed kettle (5 L) is fitted with an overheadstirrer, baffle, multi-level stirrer blade, water cooled condenser,thermocouple, bubbler and gaskets (where appropriate). All unused portsare capped with the appropriate plug. Temperature is controlled with aheating/cooling unit with the temperature controller fitted with theabove thermocouple.

Polymerization: Polyvinyl alcohol (PVA) is dispersed in a water chargeat room temperature (RT) and then heated to 70° C. The remaining salts(See Table 1, MSP, DSP, TSP, & Sodium Nitrite) are then dissolved in thewater charge. The PVA and salts solutions are heated to 80° C. withstirring. The pre-mixed organic phase including the initiator is pouredinto the reactor onto the aqueous phase with the stirring speed set atthe rpm for formation of the appropriate droplet size. Once temperaturereaches 80° C. start reaction timer (16 hours).

TABLE 1 Item Charge, g Aqueous Phase Charges Ultrapure Water 1734.47Polyvinyl Alcohol (PVA) 5.06 Monosodium Phosphate (MSP) 5.34 DisodiumPhosphate (DSP) 17.71 Trisodium Phosphate (TSP) 10.99 Sodium Nitrite0.05 Total 1773.63 Organic Phase Charges Divinylbenzene (DVB) (63%,Deltech Corp.) 592.92 Toluene 390.48 Isooctane 448.47 Benzoyl Peroxide(BPO) (97%) 4.49 Total, w/o BPO 1431.87

Work-up Mark solvent level. After cooling the solvent is siphoned out tobead level. Reactor is filled to mark with Room Temperature (RT) waterand heated to 50° C. to 70° C. and stirred for 30 minutes, allowed tosettle for 3 to 5 minutes and then siphoned out to bead level. Beads arewashed 5 times in this manner. The enteron sorbent polymer is steamstripped 6 hours and then dried in an oven overnight (˜100° C.). Thisprocess results in a clean, dry porous sorbent in the form of spherical,divinylbenzene porous polymer beads. The beads were rewet with 70% IPAand the IPA exchanged with water for further reactions under aqueousconditions.

Example 2

Reactor Setup. A 5 L kettle reactor was fitted with an over-headstirrer, baffle, a water cooled condenser, a multi-level stirrer blade,a thermocouple, and a bubbler. A gasket was installed between the toplid and bottom kettle. All unused ports were capped with the appropriateplug. Temperature was controlled with a heating mantle which wasregulated by a temperature controller fitted with the above-mentionedthermocouple.

Polymerization. Polyvinyl alcohol (“PVA”) was dispersed in one half ofthe water charge at room temperature (RT) and then heated to 70° C. Theremaining salts (See Table 2, MSP, DSP, TSP, & Sodium Nitrite) were thendissolved in the remainder of the water charge. The PVA and saltssolutions were added to the reactor and heated to 87° C. with stirring.The pre-mixed organic phase, including the initiator, was poured intothe reactor onto the aqueous phase with the stirring speed set at therevolutions per minute (“rpm”) for formation of appropriate droplet size(CY12030, 480 rpm). Once the temperature reached 87° C. the reactiontimer was set for 16 hours and started and the reaction was allowed toproceed.

TABLE 2 Item Charge, g Aqueous Phase Charges Ultrapure Water 1734.47Polyvinyl Alcohol (PVA) 5.06 Monosodium Phosphate (MSP) 5.34 DisodiumPhosphate (DSP) 17.71 Trisodium Phosphate (TSP) 10.99 Sodium Nitrite0.05 Total 1773.62 Organice Phase Charges Divinylbenzene (DVB)(63%)581.23 Cyclohexanol 1057.01 Benzoyl Peroxide (BPO)(97%) 5.91 Total, w/oBPO 1638.24

Work-up, Mark Solvent Level. After cooling, the solvent was siphoned outto the bead level. The reactor was filled to the mark with (RT) waterand heated to between 50° C. to 70° C. and stirred for 30 minutes. Thenit was allowed to settle for 3 to 5 minutes and then the liquid wassiphoned out to bead level. The beads were washed five times in thismanner. The reactor was then filled to the mark with RT methanol andstirred at RT for 5 minutes. Beads were allowed to settle for 3 to 5minutes. Beads were washed 3 times in the manner. The enteron sorbentpolymer was extracted via a soxhlet apparatus with acetone overnight.The enteron sorbent polymer was steam stripped for 8 hours and thendried in an oven overnight at approximately 100° C. This processresulted in a clean, dry porous adsorbent in the form of spherical,porous polymer beads. This material is called CY12001.

Modification Reaction. For charges see Table 3. Polymer was washed 10times with isopropyl alcohol at approximately 1 bed volume per hour andthen 10 times with purified water at approximately 1 bed volume perhour. The enteron sorbent polymer was sieved to the desired particlesize (CY12030, −106/+45 micron) and added to the reactor setup. Excesswater was siphoned to just above bed level and the charged water wasthen added. The temperature controller was set to 40° C. and thenstarted. The overhead stirrer was started as well. Each reagent wasadded while the system was ramping up to the 40° C. set point. AmmoniumPersulfate (AMPS) in water was added when the temperature was between30° C. to 34° C. NNNN-Tetramethylethylenediamine (TMED) and water wereadded between 35° C. and 36° C. Vinylpyrrolidinone (VP) and water wereadded between 39° C. and 40° C. The two hour reaction timer was startedwhen the temperature reached 40° C.; the reaction was allowed toproceed. After cooling, the solvent was siphoned out to the bead level.The beads were then washed 3 times with RT water at a rate of 1 bedvolume per half hour. The beads were steam stripped for 6 hours. Thebeads were rewet in isopropyl alcohol and washed ten times in purifiedH₂O. The enteron sorbent polymer was then dried in an oven at 100° C.

This process resulted in a clean, dry adsorbent in the form ofspherical, porous polymer beads. This material is called CY14149.

TABLE 3 CY12030 Modification of (−106/+45) CY12001 Amount of Polymerbeing modified, mL 2000 600 Charged Water, mL 721 216 AmmoniumPersulfate (AMPS), g 11.4 4.1 in Water for Addition, mL 111 33NNNN-Tetramethylethylenediamine 12.1 4.3 (TMED), g in Water forAddition, mL 55 17 Vinylpyrrolidinone (VP), g 5.9 2.1 in Water forAddition, mL 166 50 Polymer Designation CY14149 CY12031

Example 3: Pore Structure Characterization

The pore structures of the enteron sorbent polymers are analyzed with aeither Micromeritics AutoPore IV 9500 V1.09 a Mercury Penetrometer (HgIntrusion instrument) or a Micromeritics ASAP 2010 instrument (N2Desorbtion). See FIGS. 1-4.

TABLE 4 Pore volume data for CY12030 measured by Nitrogen Desorption.Pore Diameter Range Pore Volume (cc/g)  10 Å to 250,000 Å 1.6545  50 Åto 250,000 Å 1.4292 250 Å to 250,000 Å 0.9504 300 Å to 250,000 Å 0.8380500 Å to 250,000 Å 0.2352 1,000 Å to 250,000 Å  0.0088 10,000 Å to250,000 Å   0

TABLE 5 Pore volume data for CY12031 measured by Mercury Intrusion. PoreDiameter Range Pore Volume (cc/g)  10 Å to 250,000 Å 2.4016  50 Å to250,000 Å 2.4016 250 Å to 250,000 Å 2.4052 300 Å to 250,000 Å 1.9828 500Å to 250,000 Å 1.7602 1,000 Å to 250,000 Å  1.4103 10,000 Å to 250,000Å   0.3297

Additional Examples and Illustrative Embodiments

Exposure to ionizing radiation results in Acute Radiation Syndrome(ARS). Epistem have experience investigating the effects on thegastrointestinal syndrome (GI-ARS), which occurs at doses of radiationgenerally above 12 Gy (depending on the conditions/mouse strain/sizeetc). GI-ARS typically results in severe weight loss, diarrhea andeventually morbidity within 10 days of irradiation. The partial-bodyirradiation (PBI) model was used in this study. A level of 5% bonemarrow sparing was selected (PBI BM5) where the lower hind limbs(tibiae, fibulae and feet) were lead shielded during irradiation. PBImodels (2.5-5% shielding) are considered reality models for accidentalor terrorist induced exposure i.e. in such cases it is likely that asmall amount of bone marrow will be shielded in some way. The model alsohas the benefit of allowing some mice to survive long enough to enterhematological syndrome (H-ARS) and so ultimately could be used toevaluate mitigators of both syndromes.

In the current study the efficacy of a 50% slurry of enteron sorbentpolymer was evaluated to determine the effect on survival time ofC57BL/6 mice post-high dose radiation. An LD50₁₀ radiation dose of 13.5Gy was selected. This is a dose that causes 50% lethality by day 10 inundosed animals.

Aim:

To determine the efficacy of a 50% slurry of enteron sorbent polymer toincrease survival time of C57BL/6 mice following high dose (13.5 Gy)partial body irradiation.

Methods:

40 male 8-10 week old C57BL/6 mice were purchased and then randomisedinto 2 groups of 20. After acclimatising for 2 weeks they were exposedto 13.5 Gy partial-body irradiation, using a 300 kV X-ray source,shielding approximately 5% of the bone marrow (tibiae, fibulae and feetof both lower limbs). Mice were then orally gavaged twice daily with0.15 mL water or 0.15 mL 50% slurry of an enteron sorbent polymerstarting from 24 hours post-irradiation. Immediately followingadministration a further 0.15 mL of water was gavaged to all mice to aidtransit of the treatment (slurry) administration. Dosing volumesremained constant throughout the study. Animal survival, weights andincidence of diarrhea were tracked throughout the study for 15 days.

Results:

After irradiation there was, as may be expected, a rapid weight loss.Group means then plateau followed by weight recovery in the survivingmice. The group receiving an enteron sorbent polymer lost less weightthan the vehicle group, with the maximum weight lost being approximately5% less in the enteron sorbent polymer treated group. Further, the timeto reach 25% weight loss (a frequent fixed criteria for euthanasia) wasincreased by 2 days in the enteron sorbent polymer group. The mediantime to 25% weight loss was 7.5 days compared to 5.5 days in the vehiclegroup and was statistically significant (p=0.03).

The radiation dose selected was estimated to deliver an LD50₁₀ butactually achieved an LD85₁₀. This increased mortality is likely to be aresult of the extra handling/stresses associated with the oraladministrations (the LD50₁₀ is based on a radiation survival curve inuntreated mice). Administration of an enteron sorbent polymer improvedsurvival during the period of GI-ARS (i.e. up to day 10) shifting themean and median survival time by 1 day. However, this was notstatistically significant (p=0.1045). The difference between the groupsin the proportion of animals alive was greatest days 7-9 i.e. during theperiod of GI-ARS; in particular by day 8 the proportion of animals alivewas 85% for the enteron sorbent polymer group and 55% for the vehiclegroup. However, this difference did not quite reach statisticalsignificance (p=0.0824).

Upon examination of both small intestine and colon of the treated miceeuthanized on days 7-9 no trace of remaining enteron sorbent polymerbeads was observed. The sum of the diarrhea scores per group were skeweda little by one very sick animal in the control group, but were 43 inthe vehicle group (30 if the one extreme mouse is omitted) and 14 in theenteron sorbent polymer group. Group mean scores were 2.1 (1.6 if theextreme mouse omitted) in the vehicle group and 0.7 in the enteronsorbent polymer group. Fourteen mice in the vehicle group experienceddiarrhea, compared to 8 in the enteron sorbent polymer group. Withinthese animals there were 35 observed incidents in the vehicle group (28if the extreme mouse is omitted) and 12 in the enteron sorbent polymergroup. These comprised of 27 mild and 8 severe cases in the vehiclegroup (26 and 2 if the extreme mouse is omitted) and 10 mild and 2severe in the enteron sorbent polymer group. Statistical analysisconfirmed that the maximum score and average score were less in theenteron sorbent polymer group. Furthermore the mean proportion of timeperiods with diarrhea was around 7% in the enteron sorbent polymer groupcompared to around 22% in the vehicle group. The difference between thetreatments was not quite statistically significant for the maximum scoreand average score (p=0.08 and 0.06 respectively). However the differencebetween the treatments in the proportion of time periods with diarrheawas statistically significant (p=0.02).

Conclusion:

In this initial proof of concept study an enteron sorbent polymer showedefficacy in the high dose partial body irradiation model during theGI-ARS timeframe. Survival time was increased, presumably directlyrelated to the reduced weight loss following enteron sorbent polymertreatment, and diarrhea severity and duration were also reduced. Whilstall of these did not achieve statistical significance, and the level ofmortality observed was higher than that observed in non-gavaged animals(which may impact the ability to achieve a significant improvement inanimal survival numbers), the data are very encouraging and warrantfurther investigation into the possible use of enteron sorbent porouspolymers as a GI-ARS mitigator.

2. Procedures

2.1 Animals and Caging

A total of 40 C57BL/6 male mice (Harlan Laboratories, UK) were purchasedfor the study. Animals were 8-10 weeks old on supply and used at 10-12weeks of age. All mice were held in individually ventilated cages (IVCs)in an SPF (Specific Pathogen Free) barrier unit. The animals wereidentified by numbered cages and by ear punches. Handling of miceoutside of their cages was always done in a sterile laminar flowstation. A maximum of 2 cages were open at any one time.

2.2 Diet and Animal Welfare

The animals were fed a normal diet (2918× extruded diet, Harlan UK) adlibitum. Animals were maintained on acidified water from time of arrivaland throughout the study. Acid water was also used to wet the food fromday 4. There was a constant room temperature of 21±2° C. and a meanrelative humidity of 55±10%. The day-night cycle was constant, withlight and dark phases of 12 hours each (07:00 hr/19:00 hr switch).Animal health was monitored daily and cages were cleaned at regularintervals.

2.3 Radiation Parameters and Dosimetry

Based on previous studies, a dose of 13.5 Gy was selected to aim toachieve an LD50₁₀ dose.

Animals were irradiated at 15:00 hrs+/−1 hour. Irradiation was performedusing an Xstrahl RS320 X-ray set operated at 300 kV, 10 mA. The X-raytube has additional filtration to give a radiation quality of 2.3 mm Cuhalf-value layer (HVL). Mice were anaesthetised, placed in a plexiglassjig with lower hind limbs shielded and positioned at a distance of 700mm from the focus of the X-ray tube. Partial-Body Irradiation (PBI BM5)was delivered at a dose rate of 0.812 Gy/min.

X-ray output checks during the series of irradiations were measuredusing an ionizing chamber placed within the mouse restraint and showedthat for the intended machine dose of 13.5 Gy the actual dose deliveredranged from 13.48-13.58 and was therefore well within the 2% variationlimits considered acceptable.

2.4 Preparation and Administration of Vehicle

The vehicle was sterile water and was supplied as pre-prepared aliquots.

Before dosing, air bubbles within the syringe were removed by invertingthe syringe so that the bubbles rose towards the gavage needle and werethen expelled, leaving 0.15 mL water.

Vehicle was administered orally (p.o.) 24-25 hours post-irradiation andthen twice daily (10 hours apart) throughout the study. This volume of0.15 mL was not adjusted throughout the study, regardless of weightloss. Immediately following each dose of vehicle a further 0.15 mL ofwater was administered, again by oral gavage. This volume was, again,not adjusted throughout the study.

2.5 Preparation and Administration of Enteron Sorbent Polymer

Enteron sorbent porous polymer beads were supplied as pre-preparedaliquots. Enteron sorbent porous polymer beads (Sample ID: CY14149) weresupplied in seventy (70) 2 mL polypropylene tubes and stored at 4° C.upon arrival. Before dosing, the tube was inverted several times and thegavage needle placed near the bottom of the tube before drawing up thesuspension in order to avoid any empty beads floating on the surface.Air bubbles within the syringe were removed by inverting the syringe sothat the bubbles rose towards the gavage needle and were then expelled,leaving 0.15 mL enteron sorbent polymer.

The enteron sorbent polymer beads were administered orally (p.o. viagavage) 24-25 hours post-irradiation and then twice daily (10 hoursapart) throughout the study. This volume of 0.15 mL was not adjustedthroughout the study, regardless of weight loss. Immediately followingeach dose of vehicle a further 0.15 mL of water was administered, againby oral gavage. This volume was, again, not adjusted throughout thestudy.

2.6 Clinical Examinations and Weighing

Mice were weighed daily and clinical observations (diarrhea) noted dailyfrom day 4. Mice were euthanized when moribund. Any animal demonstratingmore than 15% weight loss was considered unwell and humanely euthanizedif the weight loss was sustained at greater than 20% for 24 hours andmice also demonstrated signs of a moribund state (withdrawn behavior,reduced body temperature as judged by feeling cool to touch, lack ofgrooming and dehydration as judged by a persistent skin tent onpinching). A random selection of six moribund mice from the enteronsorbent polymer group were taken for necropsy on days 7-9 to look forthe presence of test article within the intestines.

3. Results and Discussion

3.1 Weight Loss

After irradiation there was, as may be expected, a rapid weight loss.Group means then plateau followed by weight recovery in the survivingmice. The group receiving enteron sorbent polymer lost less weight thanthe vehicle group with the maximum weight lost being approximately 5%less in the enteron sorbent polymer treated group.

The weights and relative weights, plotted as a percentage of the weighton day 0, are shown in FIGS. 5 and 6.

The number of days until the weight was reduced by at least 25% from day0 was analysed in a similar manner as the time to death (see below). 25%weight loss is the level often used as euthanasia criteria, andtherefore would be reflective of an animal survival plot by many. AtEpistem it is combined with other signs of distress, since fromextensive experience it is known that animals often recover from thislevel of weight loss post irradiation. Animals that did not lose morethan 25% of their body weight were plotted by treatment group versuscontrol (FIG. 7) and the times to 25% weight loss summarized (Table 1).This showed the time to 25% weight loss to be increased by 2 days in theenteron sorbent polymer group. The median time to 25% weight loss was7.5 days compared to 5.5 days in the vehicle group. This difference wasstatistically significant (p=0.03; log-rank test).

TABLE 1 Estimates of Time to 25% Weight Loss by Treatment 95% Lower 95%Upper Treatment Median CL CL Mean Std. Err. EntericSorb 7.5 6.0 10.08.0* 0.53 Vehicle 5.5 5.0 6.0 6.3* 0.44 NE = Not estimable, *Biasedestimate

3.2 Animal Survival

The dose of radiation selected was based on previous estimates of theLD50 dose in undosed mice. The dose response curve is very steep and sothe probability of a study delivering exactly these levels of survivalis low. The twice daily oral gavages employed in the current study arelikely to have further influenced the level of lethality—since, whilstthe water will hydrate the mice, the increased handling and dosingstresses, (particularly in sick mice) may well increase mortality.

The levels of survival in the irradiated mice are plotted in FIG. 8 andillustrate that the dose estimated to deliver an LD50₁₀ actuallyachieved an LD85₁₀. All except one mouse was euthanized—the one beingfound dead in the vehicle group (mouse 18).

Kaplan-Meier survival curves of the time to death were plotted bytreatment group (FIG. 9) and the survival times summarized (Table 2).This showed the time to death to be slightly increased in the enteronsorbent polymer group. Both the mean and median time to death was 10days compared to 9 days in the vehicle group. However this differencewas not statistically significant (p=0.11; log-rank test).

TABLE 2 Estimates of Time to Death by Treatment 95% Lower 95% UpperTreatment Median CL CL Mean Std. Err. EntericSorb 710.0 9.0 11.0 10.1*0.40 Vehicle 9.0 8.0 10.0 9.1* 0.39 NE = Not estimable, *Biased estimate

The difference between the groups in the proportion of animals stillalive appeared greatest at around days 7-9 i.e. during the period ofGI-ARS; in particular by day 8 the proportion of animals alive was 85%for the enteron sorbent polymer group and 55% for the vehicle group.However, this difference did not quite reach statistical significance(p=0.08; Fisher's exact test).

Upon examination of both small intestine and colon of the treated miceeuthanized on days 7-9 no trace of enteron sorbent polymer beads wereobserved.

3.3 Diarrhea

Diarrhea was observed from day 4 and graded (where 0 was normal stoolconsistency, 1 was loose stools, 2 was severe overt diarrhea; a score of3 is liquid faeces with extended pen-anal/tail soilage). The data istabulated in the Appendix and plotted in FIG. 10 below.

The sum of the diarrhea scores per group are skewed a little by one verysick animal in the control group, but were 43 in the vehicle group (30if the one extreme mouse is omitted) and 14 in the enteron sorbentpolymer group. Group mean scores were 2.1 (1.6 if the extreme mouseomitted) in the vehicle group and 0.7 in the enteron sorbent polymergroup.

Fourteen mice in the vehicle group experienced diarrhea, compared to 8in the enteron sorbent polymer group. Within these animals there were 35observed incidents in the vehicle group (28 if the extreme mouse isomitted) and 12 in the enteron sorbent polymer group. These comprised of27 mild and 8 severe cases in the vehicle group (26 and 2 if the extrememouse is omitted) and 10 mild and 2 severe in the enteron sorbentpolymer group.

For further statistical analysis the daily diarrhea scores were used toderive three summary measures for each animal: the maximum diarrheascore, the average diarrhea score and the proportion of time periods (inthis case half-days) for which diarrhea was present (i.e., had ascore>0). These summary measures were summarized by treatment group(Table 3) and the treatment groups compared using a t-test. This showedthat the maximum score and average score were less in the enteronsorbent polymer group. Furthermore the mean proportion of time periodswith diarrhea was around 7% in the enteron sorbent polymer groupcompared to around 22% in the vehicle group.

The difference between the treatments was not quite statisticallysignificant for the maximum score and average score (p=0.08 and 0.06respectively). However the difference between the treatments in theproportion of time periods with diarrhea was statistically significant(p=0.02).

TABLE 3 Diarrhea Summary Measures by Treatment Treatment Label N MeanStd Dev Median Min Max EntericSorb Maximum score 20 0.45 0.60 0.00 0.002.0 Average score 20 0.08 0.15 0.00 0.00 0.56 Proportion of half-days 206.78 11.44 0.00 0.00 40.0 with diarrhea Maximum score 20 0.80 0.82 1.00.00 2.00 Average score 20 0.27 0.42 0.19 0.00 1.86 Proportion ofhalf-days 20 22.07 24.72 18.75 0.00 100.00 with diarrhea

4. Conclusion

In this initial proof of concept study enteron sorbent polymer showedefficacy in the high dose partial-body irradiation model during theGI-ARS timeframe. Survival time was increased, presumably directlyrelated to the reduced weight loss following enteron sorbent polymertreatment, and diarrhea severity and duration were also reduced. Thesedata demonstrate a statistical trend to benefit and are very encouragingand warrant further investigation into the possible use of enteronsorbent polymers as GI-ARS mitigators or protectants.

There are a variety of options for further studies, each with aim ofdemonstrating increased efficacy, predominantly on animal survivalnumber at a given timepoint (the actual timepoint may be defined as anappropriate time during GI-ARS—typically day 6-8 in a TBI model,extending towards day 10 in a PBI BM5 model). Thus, a statisticallysignificant increase from a given LD (e.g. LD50) on day 8 (definedLD50₈) should be demonstrated. In a TBI model of GI-ARS all animals willultimately die, even if mitigated somewhat, due to H-ARS. Thus, the PBImodel is designed such that animals that survive the early stage GI-ARSwill maintain sufficient bone marrow function to also survive the laterstage H-ARS. Either is an appropriate and acceptable model fordemonstrating efficacy during the GI-ARS timeframe.

In order to increase efficacy options include:

1. Reducing the number or duration of gavage administrations (assumingthat this is increasing mortality due to handling stresses in sickmice). The severity of the handling stress may be offset a little by therehydration effects, and so both need to be considered.

2. Reducing the radiation dose (remaining within the GI toxicity rangebut accepting that a lower dose may be closer to an LD50₈₋₁₀ and less ofa challenge for any prospective mitigator to ‘rescue’). Clearly theanimal survival dose response curve is unknown for this administrationschedule, but we do know that the LD curve is steep, and so a smallreduction to 13 Gy may be sufficient.

3. Moving from a PBI to a TBI model—generally tougher to rescue butenteron sorbent polymer beads may behave differently in this model,given the lack of immunological competence (bone marrow survival) andincreased risk of septicaemia. The profile of sequestration of bothcytokines and bacterial toxins may be different.

Ultimately, once further efficacy is demonstrated, confirmation of themechanism of action will be needed (demonstration of improvedhistopathology, reduction in bacterial toxins, demonstration of improvedcytokine profile etc).

5.1 Animal Weights Mouse Day Day Day Day Day Day Day Day Day Day Day DayDay Day Day Day Treatment Number 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1513.5Gy PBI BM5 1 27.3 26.1 25.6 23.8 23.3 21.9 20.9 20.9 Vehicle 2 27.125.4 25.1 23.7 22.9 20.2 19.4 19.5 3 29.2 28.0 27.7 25.7 24.4 22.9 22.022.2 22.4 22.2 21.3 20.4 19.4 4 27.1 26.4 25.9 24.0 22.5 20.6 19.6 18.95 26.9 25.8 25.5 24.4 23.1 21.0 20.5 21.0 22.5 22.6 18.9 6 26.3 24.524.4 22.6 21.7 19.6 19.0 18.8 18.8 7 27.4 26.6 26.5 24.7 23.1 21.0 20.118.5 8 26.7 25.4 25.2 23.5 22.7 21.3 21.3 22.0 23.5 23.1 23.4 22.9 23.623.2 22.8 22.3 9 26.7 25.3 24.7 23.2 22.1 20.1 19.5 19.5 17.9 10 28.326.4 25.9 24.1 22.5 20.7 19.9 20.5 19.7 11 26.1 24.7 23.8 21.7 20.3 19.318.2 17.8 16.0 12 28.5 26.8 27.1 24.6 23.1 20.8 20.4 19.9 18.5 13 26.425.3 25.1 23.4 21.9 20.1 19.3 14 27.4 25.8 25.5 23.3 21.4 20.2 20.0 20.119.4 18.9 15 27.6 25.8 25.3 23.9 21.8 20.5 19.3 18.4 16 26.6 24.8 25.223.1 21.6 19.7 19.7 19.7 19.9 20.1 17 26.0 25.2 25.0 22.9 21.3 19.7 19.218.8 18 25.5 24.0 23.8 22.2 20.8 19.1 19 27.2 25.0 25.0 23.3 22.0 20.319.7 18.3 20 28.5 26.9 26.9 25.1 23.0 21.6 21.0 20.4 19.7 19.8 Mean 27.125.7 25.5 23.7 22.3 20.5 19.9 19.7 19.8 21.1 21.2 21.7 21.5 23.2 22.822.3 SD 0.9 1.0 1.0 1.0 1.0 0.9 0.9 1.3 2.2 1.7 2.3 1.8 3.0 13.5Gy PBIBM5 21 28.2 27.3 26.9 25.2 24.1 23.0 22.7 21.4 19.6 EntericSorb 22 26.525.1 25.3 22.0 20.7 19.4 19.8 20.1 20.3 19.4 18.3 23 25.7 23.9 24.1 21.920.8 19.0 18.5 17.6 24 28.2 27.8 27.7 26.1 24.8 23.8 23.3 23.6 23.2 21.525 27.6 26.2 26.0 23.9 22.3 20.2 19.4 26 26.8 24.8 24.6 23.5 22.8 21.020.7 19.8 19.0 18.0 27 27.7 25.9 26.0 25.3 23.9 22.3 21.2 20.6 19.5 2826.8 25.8 25.4 24.1 23.3 21.7 20.5 21.2 21.1 21.1 19.0 29 27.9 26.6 26.225.0 24.0 21.7 21.1 20.6 19.0 30 27.6 25.1 25.5 23.7 23.2 21.7 20.8 21.220.3 19.7 31 27.5 26.1 26.6 24.6 23.1 21.7 20.7 19.7 19.3 32 28.0 27.427.9 25.6 24.2 22.7 22.1 22.2 19.8 18.5 33 26.8 25.8 25.9 23.7 22.5 21.220.9 22.0 22.6 22.7 21.0 18.4 34 27.8 26.0 26.4 25.2 23.5 21.2 20.2 21.219.4 35 26.3 24.1 25.1 23.2 21.9 20.1 20.0 21.1 21.8 22.7 20.3 20.0 3627.7 26.0 26.2 24.6 22.7 21.5 20.6 21.5 20.3 37 28.1 27.0 26.2 24.8 23.121.7 21.8 23.7 24.4 24.8 24.0 24.6 22.9 21.7 23.5 23.7 38 25.4 24.4 24.822.4 20.7 19.0 18.7 18.0 39 27.9 27.3 27.1 25.7 24.2 22.6 21.4 22.8 23.524.4 23.9 24.2 23.9 24.0 23.9 23.8 40 26.3 25.2 25.9 24.1 22.4 20.6 20.520.9 20.8 21.9 21.2 19.7 18.3 Mean 27.2 25.9 26.0 24.2 22.9 21.3 20.721.0 20.8 21.3 21.1 21.4 21.7 22.9 23.7 23.8 SD 0.9 1.1 1.0 1.2 1.2 1.31.2 1.6 1.7 2.3 2.2 2.8 3.0 1.6 0.3 0.1

5.2 Animal Weights As A Percentage of 0 Mouse Day Day Day Day Day DayDay Day Day Day Day Day Day Day Day Day Treatment Number 0 1 2 3 4 5 6 78 9 10 11 12 13 14 15 13.5Gy PBI BM5 1 100.0 95.6 93.8 87.2 85.3 80.276.6 76.6 Vehicle 2 100.0 93.7 92.6 87.5 84.5 74.5 71.6 72.0 3 100.095.9 94.9 88.0 83.6 78.4 75.3 76.0 76.7 76.0 72.9 69.9 66.4 4 100.0 97.495.6 88.6 83.0 76.0 72.3 69.7 5 100.0 95.9 94.8 90.7 85.9 78.1 76.2 78.183.6 84.0 70.3 6 100.0 93.2 92.8 85.9 82.5 74.5 72.2 71.5 71.5 7 100.097.1 96.7 90.1 84.3 76.6 73.4 67.5 8 100.0 95.1 94.4 88.0 85.0 79.8 79.882.4 88.0 86.5 87.6 85.8 88.4 86.9 85.4 83.5 9 100.0 94.8 92.5 86.9 82.875.3 73.0 73.0 67.0 10 100.0 93.3 91.5 85.2 79.5 73.1 70.3 72.4 69.6 11100.0 94.6 91.2 83.1 77.8 73.9 69.7 68.2 61.3 12 100.0 94.0 95.1 86.381.1 73.0 71.6 69.8 64.9 13 100.0 95.8 95.1 88.6 83.0 76.1 73.1 14 100.094.2 93.1 85.0 78.1 73.7 73.0 73.4 70.8 69.0 15 100.0 93.5 91.7 86.679.0 74.3 69.9 66.7 16 100.0 93.2 94.7 86.8 81.2 74.1 74.1 74.1 74.875.6 17 100.0 96.9 96.2 88.1 81.9 75.8 73.8 72.3 18 100.0 94.1 93.3 87.181.6 74.9 19 100.0 91.9 91.9 85.7 80.9 74.6 72.4 67.3 20 100.0 94.4 94.488.1 80.7 75.8 73.7 71.6 69.1 69.5 Mean 100.0 94.7 93.8 87.2 82.1 75.673.3 72.4 72.5 76.8 76.9 77.8 77.4 86.9 85.4 83.5 SD 0.0 1.5 1.6 1.8 2.42.1 2.5 4.1 7.9 7.3 9.4 11.2 15.5 13.5Gy PBI BM5 21 100.0 96.8 95.4 89.485.5 81.6 80.5 75.9 69.5 EntericSorb 22 100.0 94.7 95.5 83.0 78.1 73.274.7 75.8 76.6 73.2 69.1 23 100.0 93.0 93.8 85.2 80.9 73.9 72.0 68.5 24100.0 98.6 98.2 92.6 87.9 84.4 82.6 83.7 82.3 76.2 25 100.0 94.9 94.286.6 80.8 73.2 70.3 26 100.0 92.5 91.8 87.7 85.1 78.4 77.2 73.9 70.967.2 27 100.0 93.5 93.9 91.3 86.3 80.5 76.5 74.4 70.4 28 100.0 96.3 94.889.9 86.9 81.0 76.5 79.1 78.7 78.8 70.9 29 100.0 95.3 93.9 89.6 86.077.8 75.6 73.8 68.1 30 100.0 90.9 92.4 85.9 84.1 78.6 75.4 76.8 73.671.4 31 100.0 94.9 96.7 89.5 84.0 78.9 75.3 71.6 70.2 32 100.0 97.9 99.691.4 86.4 81.1 78.9 79.3 70.7 66.1 33 100.0 96.3 96.6 88.4 84.0 79.178.0 82.1 84.3 84.7 78.4 68.7 34 100.0 93.5 95.0 90.6 84.5 76.3 72.776.3 69.8 35 100.0 91.6 95.4 88.2 83.3 76.4 76.0 80.2 82.9 86.3 77.276.0 36 100.0 93.9 94.6 88.8 81.9 77.6 74.4 77.6 73.3 37 100.0 96.1 93.288.3 82.2 77.2 77.6 84.3 86.8 88.3 85.4 87.5 81.5 77.2 83.6 84.3 38100.0 96.1 97.6 88.2 81.5 74.8 73.6 70.9 39 100.0 97.8 97.1 92.1 86.781.0 76.7 81.7 84.2 87.5 85.7 86.7 85.7 86.0 85.7 85.3 40 100.0 95.898.5 91.6 85.2 78.3 77.9 79.5 79.1 83.3 80.6 74.9 69.6 Mean 100.0 95.095.4 88.9 84.1 78.2 76.1 77.1 76.0 78.4 78.2 78.8 78.9 81.6 84.6 84.8 SD0.00 2.1 2.1 2.5 2.5 3.0 2.9 4.4 6.3 8.2 6.5 8.1 8.3 6.2 1.4 0.7

5.3 Diarrhea Scores Mouse Treat- Num- Day 4 Day 5 Day 6 Day 7 Day 8 Day9 Day 10 Day 11 Day 12 Day 13 Day 14 ment ber AM PM AM PM AM PM AM PM AMPM AM PM AM PM AM PM AM PM AM PM AM PM 13.5Gy 1 0 0 0 0 1 0 0 0 PBI 2 00 0 0 1 0 0 0 BM5 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Vehicle 4 0 0 1 01 0 0 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 0 1 1 0 1 0 0 0 0 0 7 0 0 1 0 1 00 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9 0 0 1 0 0 0 0 0 0 0 100 0 0 0 0 0 0 0 0 11 0 0 0 0 0 0 0 0 0 12 0 1 2 2 1 0 1 0 0 13 0 1 1 0 10 14 0 0 1 1 1 0 0 0 0 0 0 15 2 2 2 2 2 2 1 16 0 0 0 0 1 0 0 0 0 0 0 170 0 0 0 0 0 0 0 18 0 0 0 1 19 0 1 0 0 1 0 0 0 20 0 1 1 0 1 0 0 0 0 0 0SUM 2 7 11  6 13  2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13.5Gy 21 0 0 0 0 00 0 0 0 PBI 22 0 0 0 0 0 0 0 0 0 0 0 0 0 0 BM5 23 0 1 0 0 0 0 0 0 Enter-24 0 0 0 0 0 0 0 0 0 0 0 icSorb 25 0 0 1 0 1 26 0 0 0 0 0 0 0 0 0 0 0 270 0 0 0 0 0 0 0 0 0 28 0 0 0 0 0 0 0 0 0 0 0 0 0 29 0 0 1 0 0 0 0 0 0 300 0 0 0 0 0 0 0 0 0 0 0 31 0 0 0 0 0 0 0 0 0 0 32 0 0 0 0 0 0 0 0 0 0 033 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 34 0 2 2 0 1 0 0 0 0 35 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 36 0 0 1 0 0 0 0 0 0 0 37 0 0 0 0 1 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 38 0 0 1 0 0 0 0 0 39 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 40 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 SUM 3 7 0 4 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0

What is claimed:
 1. A method comprising gastrointestinal administrationof one or more enteron sorbent polymers to a subject that was exposed toradiation; wherein said enteron sorbent polymer is characterized ashaving a pore structure having a total volume of pore sizes in the rangeof from 10 Å to 250,000 Å greater than 0.3 cc/g to 3.0 cc/g dry polymer;wherein the ratio of pore volume between 10 Å to 250,000 Å in diameterto pore volume between 250 Å to 250,000 Å in diameter of thecross-linked polymeric material is smaller than 7:1 and wherein theratio of pore volume between 10 Å to 250,000 Å in diameter to porevolume between 50 Å to 250,000 Å in diameter of the cross-linkedpolymeric material is less than 2:1.
 2. The method of claim 1 where theradiation source of is cancer therapy.
 3. The method of claim 1 wherethe source of radiation is gamma radiation, X-rays, or cosmic radiation,transmitted via radiation or through contamination of the air, food, orwater.
 4. The method of claim 1 wherein said enteron sorbent polymercomprises cross-linked polymeric material derived from the reaction of across-linker with one or more of the following polymerizable monomers:styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octylmethacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate, cetylacrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene,vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methylmethacrylate, and methyl acrylate.
 5. The method of claim 1 where theenteron sorbent polymers are administered via capsule, tablet, salve,poultice, in slurry form, suppository, or enema, via oral, rectal,nasogastric or gastric tube, or ostomy routes.
 6. The method of claim 1where the enteron sorbent polymers remove inflammatory mediators,comprising cytokines, superantigens, monokines, chemokines, interferons,free radicals, proteases, arachidonic acid metabolites, prostacyclins,beta endorphins, anandimide, 2-arachadonylglycerol, tetrahydrobiopterin,serotonin, histamine, bradykinin, soluble CD40 ligand, bioactive lipids,oxidized lipids, cell-free hemoglobin, growth factors, glycoproteins,prions, toxins, bacterial and viral toxins, endotoxins, drugs,vasoactive substances, foreign antigens, and antibodies from the gutlumen.
 7. The method of claim 1 where the enteron sorbent polymers arebiocompatible.
 8. The method of claim 1 where the enteron sorbentpolymers are in the form of a powder, suspension, beads or otherregularly or irregularly shaped particulates.
 9. The method of claim 1where the enteron sorbent polymers have a diameter in the range of 0.1microns to 2 centimeters.
 10. The method of claim 1 where the enteronsorbent polymers are gamma radiation stable.
 11. The method of claim 1where the enteron sorbent polymers are gamma radiation stable and can beadministered prior or concurrently to radiotherapy.
 12. The method ofclaim 1 where the enteron sorbent polymers do not absorb or minimallyabsorb radiation (radiolucent) and therefore do not affect theradiotherapy dose to treat diseases.
 13. The method of claim 1 where theenteron sorbent polymers absorb radiation (radiopaque) and provideadditional radioprotection.
 14. The method of claim 1 where the enteronsorbent polymers function as radioprotectants that enable higher andpotentially more effective doses of radiotherapy, or more doses ofradiotherapy, to treat cancer while mitigating acute radiation enteritisor colitis.
 15. A method comprising gastrointestinal administration ofone or more enteron sorbent polymers to a subject prior to exposure toradiation, wherein said enteron sorbent polymer is characterized ashaving a pore structure having a total volume of pore sizes in the rangeof from 10 Å to 250,000 Å greater than 0.3 cc/g to 3.0 cc/g dry polymer;wherein the ratio of pore volume between 10 Å to 250,000 Å in diameterto pore volume between 250 Å to 250,000 Å in diameter of thecross-linked polymeric material is smaller than 7:1 and wherein theratio of pore volume between 10 Å to 250,000 Å in diameter to porevolume between 50 Å to 250,000 Å in diameter of the cross-linkedpolymeric material is less than 2:1.
 16. The method of claim 15, wherethe radiation is a component of cancer therapy.
 17. The method of claim15, wherein said enteron sorbent polymer comprises cross-linkedpolymeric material derived from the reaction of a cross-linker with oneor more of the following polymerizable monomers: styrene, ethylstyrene,acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate,octyl acrylate, cetyl methacrylate, cetyl acrylate, ethyl methacrylate,ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol,vinylformamide, methyl methacrylate, and methyl acrylate.
 18. The methodof claim 15, where the enteron sorbent polymers are administered viacapsule, tablet, salve, poultice, in slurry form, suppository, or enema,via oral, rectal, nasogastric or gastric tube, or ostomy routes.
 19. Themethod of claim 15, where the enteron sorbent polymers arebiocompatible.
 20. The method of claim 15, where the enteron sorbentpolymers are in the form of a powder, suspension, beads or otherregularly or irregularly shaped particulates.
 21. The method of claim15, where the enteron sorbent polymers have a diameter in the range of0.1 microns to 2 centimeters.
 22. The method of claim 15, where theenteron sorbent polymers are gamma radiation stable.